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首页> 外文期刊>Mutation Research: International Journal on Mutagenesis, Chromosome Breakage and Related Subjects >Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide inactivation in human hepatoma cells.
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Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide inactivation in human hepatoma cells.

机译：二恶英通过细胞色素P450 1A1诱导抑制苯并[a]芘诱导的突变和DNA加合物形成，（±） - 丙烯-7,8-Diol-9,10-环氧化灭活在人肝癌细胞中。

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Benzo[a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine-guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP-DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE-DNA adduct formation. Further experiments using "Tet-On" cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA-reactive, thereby reducing mutations in hepatoma cells.
机译：通过细胞色素P450酶来代谢激活苯并[a]芘（BAP），形成导致突变的DNA加合物。细胞色素P450 1A1在该活化步骤中起核心作用，并且该酶通过结合芳基烃受体（AHR）的化学试剂强烈诱导，所述芳基烃受体（AHR）也称为二恶英受体。 2,3,7,8-四氯二氯二苯甲苯-P-二恶英（TCDD），尚未显示出效率的AHR配体形成任何DNA加合物，但是可以通过诱导代谢酶来加剧前一种多环烃的毒性。我们用TCDD处理人肝癌细胞（HepG2），随后将它们暴露在释放它们以阐明对突变的协同作用。令人惊讶的是，通过用TCDD预处理降低，在次黄嘌呤 - 鸟嘌呤磷酰基转移酶（HPRT）基因座上诱导的突变频率降低。在与突变频率的降低的相关性中，通过TCDD预处理也降低了BAP-DNA加合物。当细胞暴露于（±） - 苯并[a]芘-7,8-diol-9,10-环氧化（BPDE）时，TCDD的这种抑制作用更有效，该蛋酯-7,8-Diol-9,10-环氧化学物质的反应性代谢中间体。在催化烘焙氧化和缀合的酶中，通过暴露于TCDD诱导细胞色素P450 1A1,1A2,3A4和UDP-葡糖醛醛糖基转移酶1A1MRNA。在细胞色素P450 1A1 - 缺乏鼠细胞和细胞色素P450 1A1-不可欺骗的人体细胞中，TCDD不能抑制BPDE-DNA加合物。使用“TET-ON”细胞色素P450 1A1-过表达细胞和重组细胞色素P4501A1酶的进一步实验证明这是携带的BAP的生物转化中涉及的关键酶，即BPDE的生产和灭活。我们得出结论，TCDD诱导的细胞色素P450催化BPDE的代谢为尚未明显DNA反应的尚未识别的产物，从而减少肝癌细胞中的突变。

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